Purpose

Dipeptidyl peptidase 4 (DPP₄) inactivates a range of bioactive peptides. The cleavage of insulinotropic peptides and glucagon-like peptide 1 (GLP₁) by DPP₄ directly influences glucose homeostasis. This study aimed to describe the mode of interaction between sitagliptin (an antidiabetic drug) and human DPP₄ using in silico approaches.

Materials and methods

Docking studies were conducted using AutoDock Vina, 2D and 3D schematic drawings were obtained using PoseView and PLIP servers, and the DPP₄-sitagliptin complex was visualized with Pymol software.

Results

The best affinity energy to form the DPP₄-sitagliptin complex was E-value ​= ​- 8.1 ​kcal ​mol⁻¹, as indicated by docking simulations. This result suggests a strong interaction. According to our observations, hydrophobic interactions involving the amino acids residues Tyr⁶⁶³ and Val⁷¹², hydrogen bonds (Glu²⁰³, Glu²⁰⁴, Tyr⁶⁶³, and Tyr⁶⁶⁷), π-Stacking interactions (Phe³⁵⁵ and Tyr⁶⁶⁷), and halogenic bonds (Arg¹²³, Glu²⁰⁴, and Arg³⁵⁶) were prevalent in the DPP₄-sitagliptin complex. Root Mean Square Deviation prediction also demonstrated that the global structure of the human DPP₄ did not have a significant change in its topology, even after the formation of the DPP₄-sitagliptin complex.

Conclusion

The stable interaction between the sitagliptin ligand and the DPP₄ enzyme was demonstrated through molecular docking simulations. The findings presented in this work enhance the understanding of the physicochemical properties of the sitagliptin interaction site, supporting the design of more efficient gliptin-like iDPP₄ inhibitors.

中文翻译：

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西他列汀与人 DPP4 酶的分子相互作用机制 - 新见解

目的

二肽基肽酶 4 (DPP ₄ ) 可使一系列生物活性肽失活。DPP _{4对促胰岛素肽和胰高血糖素样肽 1 (GLP 1} )的裂解直接影响葡萄糖稳态。本研究旨在使用计算机_{方法描述西他列汀（一种抗糖尿病药物）和人 DPP 4}之间的相互作用模式。

材料和方法

使用 AutoDock Vina 进行对接研究，使用 PoseView 和 PLIP 服务器获得 2D 和 3D 示意图，并使用 Pymol 软件可视化DPP _{4 -西他列汀复合物。}

结果

对接模拟表明，形成 DPP ₄ -西格列汀复合物的最佳亲和能为E值​= ​- 8.1 ​kcal ​mol ^{−1 。}这一结果表明存在很强的相互作用。根据我们的观察，涉及氨基酸残基 Tyr ⁶⁶³和 Val ^{712的疏水相互作用}、氢键（Glu ²⁰³、Glu ²⁰⁴、Tyr ⁶⁶³和 Tyr ⁶⁶⁷）、π-堆积相互作用（Phe ³⁵⁵和 Tyr ⁶⁶⁷）和卤键（Arg ¹²³、Glu ²⁰⁴和 Arg ^{356 ）在 DPP} ₄ -西他列汀复合物中普遍存在。均方根偏差预测还表明，即使在DPP 4 -西他列汀复合物形成之后，人类DPP 4 的整体结构_在其拓扑上也没有显着变化。

结论

通过分子对接模拟证明了西格列汀配体和 DPP _{4酶之间的稳定相互作用}。这项工作中提出的结果增强了对西格列汀相互作用位点的理化性质的理解，支持设计更有效的格列汀样 iDPP ₄抑制剂。